The present invention relates to a method for treating mastitis in a domestic animal (mammal), a therapeutic medicament for, or use of certain rifamycin derivatives for the manufacture of a therapeutic medicament for mastitis in a domestic animal. More particularly, the invention relates to a method for treating an inflammatory disease caused by infection with a bacterium in the mammary gland of a domestic animal such as a dairy cow or a goat, which comprises administering to the animal a pharmaceutical composition comprising as an active ingredient a rifamycin derivative or a physiologically acceptable salt thereof, and a physiologically acceptable carrier. Also, the present invention provides a therapeutic medicament for mastitis in a domestic mammal which comprises said rifamycin derivative, or use of said derivative for the manufacture of said therapeutic medicament.
Mastitis in domestic animals raised for obtaining milk such as a dairy cow and a goat is a disease in which the mammary glands in the animals are infected with Staphylococcus (e.g., Staphylococcus aureus), Escherichia coli, or another pathogenic bacterium causing inflammation; or a disease related to such a bacterium. Mastitis is a very costly disease for the dairy industry due to its high incidence, and the resulting reduced milk production, reduced milk quality and increased culling (removal) of animals from dairy herds.
As described above, mastitis is a very serious disease in domestic animals, and a known therapy frequently used is the administration by infusion of an antimicrobial drug directly into the mammary gland of a domestic animal affected with mastitis. Most of the mastitis is cured or alleviated by such an infusion for treating mastitis. However, due to a change in the kind of bacterium causing mastitis and a lowering of susceptibility of a bacterium causing mastitis to existing antimicrobial drugs for treating mastitis, at present mastitis for which no therapeutic effect is obtained by known drugs has increased.
For instance, cefazolin which is a first-generation cephalosporin antibiotic has been used for treating this disease. However, cases wherein treatment of mastitis is difficult have increased because bacteria resistant to this antibiotic have appeared and increased at present. Also, although cefem antibiotics and the like have been used, their effect is not sufficient for treating mastitis. In order to develop more effective therapy, it is necessary to introduce a new, more effective therapeutic agent.
An object of the present invention is to provide a method for treating mastitis in a domestic animal in need of such a treatment, which comprises administering to the animal a pharmaceutical composition comprising a rifamycin derivative of the formula (1): 
wherein R is an alkyl group having 1 to 7 carbon atoms or a physiologically acceptable salt thereof as an active ingredient, and a physiologically acceptable carrier. Also, the present invention provides a therapeutic medicament for mastitis in a domestic mammal which comprises said rifamycin derivative, or use of said derivative for the manufacture of said therapeutic medicament.
This and other objects of the present invention will become apparent from the following description.
In accordance with the present invention, there is provided a method for treating mastitis in a domestic animal in need of such a treatment, which comprises administering to the animal a pharmaceutical composition comprising a rifamycin derivative of the formula (1): 
wherein R is an alkyl group having 1 to 7 carbon atoms or a physiologically acceptable salt thereof as an active ingredient, and a physiologically acceptable carrier. Also the present invention provides a therapeutic medicament for mastitis in a domestic mammal comprising said rifamycin derivative or use of said derivative for the manufacture of said therapeutic medicament.
The alkyl group having 1 to 7 carbon atoms in R in the rifamycin derivative (1) used in the present invention includes linear, branched and cyclic alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, pentyl group, isopentyl group, sec-pentyl group, tert-pentyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, cyclopentyl group, cyclobutylmethyl group, hexyl group, 4-methylpentyl group, cyclohexyl group, 3-methylcyclopentyl group, heptyl group, isoheptyl group, and the like. Methyl, ethyl, propyl, isopropyl, cyclopropyl and isobutyl groups are preferred.
The rifamycin derivative (1) used in the present invention for treating mastitis in a domestic animal can be obtained by methods disclosed in, for example, Japanese Examined Patent Publication (Kokoku) No. 57275/1993, Japanese Unexamined Patent Publication (Kokai) Nos. 007291/1991, 101681/1991 and 03589/1992, and Chem. Pharm. Bull., Vol. 41, 148 (1993), and the like.
The rifamycin derivative (1) is able to form a salt with either an acid or a base. As the acid or base which can be used for the salt formation, any one capable of forming a salt with the rifamycin derivative (1) can be used. Examples of the salt with a base are (1) metal salts, particularly alkali metal salts such as sodium salts and potassium salts and alkaline earth metal salts such as calcium salts, (2) ammonium salts, and (3) amine salts, particularly salts with methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, morpholine and hexamethyleneimine, and the like. Examples of the salt with an acid are (1) salts with mineral acids such as sulfuric acid and hydrochloric acid, and (2) salts with organic acids such as p-toluenesulfonic acid, trifluoroacetic acid and acetic acid.
A physiologically acceptable salt of the rifamycin derivative (1) which can be used in the present invention is selected from the above-mentioned salts which are physiologically acceptable.
The domestic animal to be treated in the present invention is preferably an animal kept and/or fed for obtaining milk, such as a dairy cow or a goat.
Each of the rifamycin derivatives (1) wherein each R is methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group or isobutyl group was orally administered to mice in a dose of 1,000 mg/kg. They did not show any toxicity, so it was confirmed that the rifamycin derivatives shown by the formula (1) have low toxicity.
The pharmaceutical composition used according to the present invention is administered orally or parenterally. In case of parenteral administration of the above-mentioned composition to a domestic animal in need of treatment for mastitis according to the present invention, the composition may be injected or infused hypodermically, intradermally, intramuscularly or through the lactiferous duct in the form of an injection preparation or an infusion preparation. However, the administration route is not limited to these examples.
The pharmaceutical composition which contains as an active ingredient the rifamycin derivative (1), or its physiologically acceptable salt, used according to the present invention may be, for example, in the form of an injection preparation or an infusion preparation such as an aqueous suspension preparation, an oily suspension preparation, an emulsion preparation or a solution preparation. The above-mentioned composition used according to the present invention may also be, for example, in the form of a preparation for oral administration such as powder, tablets including sugar-coated tablets, capsules, pills, fine granules, granules or syrup. A physiologically acceptable carrier contained in the pharmaceutical composition used in the present invention may be any carrier including a solvent which is usually used for preparing a pharmaceutical composition in the art. A solvent used in the injection or infusion preparation according to the present invention includes water, a water-miscible solvent and an oily solvent. Examples of the water-miscible solvent are ethanol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerol and other solvents miscible with water in any preparation. Preferably ethanol and benzyl alcohol, and more preferably benzyl alcohol is used. As the oily solvent, any one in liquid form at ordinary temperatures, such as a vegetable oil or a fatty acid ester, can be used. Examples of the vegetable oil are purified olive oil, peanut oil, sesame oil, camellia oil, and the like. However, the solvent is not limited thereto.
To the suspension preparations may be added a surfactant such as a polysorbate. In order to prepare an emulsion preparation, a surfactant such as a sorbitan fatty acid ester, benzalkonium chloride or polyoxyethylene hydrogenated castor oil may be used. Also, the carriers used for preparing the pharmaceutical composition used according to the present invention include organic or inorganic, solid or liquid, usually inactive pharmaceutical carriers suitable for oral administration. Examples of the carrier are crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal oils and fats, gums, polyalkylene glycols, and the like. However, the carrier is not limited thereto. The amount of the active ingredient (effective component) in the pharmaceutical composition used according to the present invention in the preparations can be varied within the range of 0.2 to 50% by weight based on the carrier. The pharmaceutical composition used in the present invention may contain one or more other therapeutic agent for treating mastitis in a domestic animal and/or other medicaments, which are compatible therewith. In that case, needless to say, the rifamycin derivative (1) or its physiologically acceptable salt does not have to be the main ingredient in the preparations.
The pharmaceutical composition used in the present invention is generally administered in such a dosage as to achieve the desired actions, i.e. in an effective amount without any side effect.
A concrete dosage of the composition used according to the present invention should be determined by a veterinarian. In an infusion preparation to be administered through the lactiferous duct or an injection preparation to be administered to a mammary gland or a vein, however, an amount in the range of about 1 mg-about 10 g, preferably in the range of about 5 mg-about 5 g, on the basis of the rifamycin derivative (1) may be usually administered per day per mammary gland of a cow.
In an oral preparation, an amount in the range of about 500 mg-about 50 g, preferably in the range of about 1 g-about 30 g, on the basis of the rifamycin derivative (1) may be usually administered per day per cow. The pharmaceutical composition used in the present invention may be administered as a pharmaceutical preparation which contains 1 mg-50 g, preferably 2 mg-10 g, on the basis of the rifamycin derivative (1) in a dosage unit.
The present invention is more specifically described and explained by means of the following Examples and Preparation Examples, but it is to be understood that the present invention is not limited to these examples.
In the following examples, the rifamycin derivatives (1) were prepared according to U.S. Pat. No. 4,983,602 and rifampin was obtained from Sigma Chemical Company.